Alzheimer's disease (AD) is the sixth leading cause of death globally in which abnormal phosphorylation of tau proteins may be the most pathological hallmark. Tau proteins are phosphoproteins which may be moderately phosphorylated under physiological conditions but their hyperphosphorylation reflects the pathogenicity. There are, generally, around 85 phosphorylation sites on tau but it is elusive which phosphorylation event may be the most critical step toward the pathogenicity.
Tau protein phosphorylated at threonine residue 231 (pT231-tau) is one of the hyperphosphorylated forms of tau protein which exist in the two distinct cis and trans conformation. Recent studies in mice show that cis conformation of the pT231-tau protein may be considered as a pathologic tau protein and may cause neurodegeneration upon traumatic brain injury (TBI). However, studies of exemplary embodiments of the present disclosure demonstrate that neither cis nor trans conformations of the pT231-tau proteins accumulate in human brains with Alzheimer's disease (AD). As a result, neurotoxic pT231-tau proteins in human with Alzheimer's disease may have an intermediate structure different from cis or trans conformations.
There is, therefore, a need for conformation-independent antibodies which specifically bind to neurotoxic pT231-tau proteins. There is also a need for efficient methods and kits for screening, diagnosing, and treating Alzheimer's disease using conformation-independent antibodies against neurotoxic pT231-tau proteins.